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Lactate produced during labor modulates uterine inflammation via GPR81 (HCA1).

Abstract：

BACKGROUND:Uterine inflammatory processes trigger prolabor pathways and orchestrate on-time labor onset. Although essential for successful labor, inflammation needs to be regulated to avoid uncontrolled amplification and resolve postpartum. During labor, myometrial smooth muscle cells generate ATP mainly via anaerobic glycolysis, resulting in accumulation of lactate. Aside from its metabolic function, lactate has been shown to activate a G protein-coupled receptor, GPR81, reported to regulate inflammation. We therefore hypothesize that lactate produced during labor may act via GPR81 in the uterus to exert in a feedback manner antiinflammatory effects, to resolve or mitigate inflammation. OBJECTIVE:We sought to investigate the role of lactate produced during labor and its receptor, GPR81, in regulating inflammation in the uterus. STUDY DESIGN:We investigated the expression of GPR81 in the uterus and the pharmacological role of lactate acting via GPR81 during labor, using shRNA-GPR81 and GPR81-/- mice. RESULTS:(1) Uterine lactate levels increased substantially from 2 to 9 mmol/L during labor. (2) Immunohistological analysis revealed expression of GPR81 in the uterus with high expression in myometrium. (3) GPR81 expression increased during gestation, and peaked near labor. (4) In primary myometrial smooth muscle cell and ex vivo uteri from wild-type mice, lactate decreased interleukin-1β-induced transcription of key proinflammatory Il1b, Il6, Ccl2, and Pghs2; suppressive effects of lactate were not observed in cells and tissues from GPR81-/- mice. (5) Conversely, proinflammatory gene expression was augmented in the uterus at term in GPR81-/- mice and wild-type mice treated intrauterine with lentiviral-encoded shRNA-GPR81; GPR81 silencing also induced proinflammatory gene transcription in the uterus when labor was induced by endotoxin (lipopolysaccharide). (6) Importantly, administration to pregnant mice of a metabolically stable specific GPR81 agonist, 3,5-dihydroxybenzoic acid, decreased endotoxin-induced uterine inflammation, preterm birth, and associated neonatal mortality. CONCLUSION:Collectively, our data uncover a novel link between the anaerobic glycolysis and the control of uterine inflammation wherein the high levels of lactate produced during labor act on uterine GPR81 to down-regulate key proinflammatory genes. This discovery may represent a novel feedback mechanism to regulate inflammation during labor, and conveys a potential rationale for the use of GPR81 agonists to attenuate inflammation and resulting preterm birth.

journal_name

Am J Obstet Gynecol

journal_title

American journal of obstetrics and gynecology

authors

Madaan A,Nadeau-Vallée M,Rivera JC,Obari D,Hou X,Sierra EM,Girard S,Olson DM,Chemtob S

doi

10.1016/j.ajog.2016.09.072

subject

Has Abstract

pub_date

2017-01-01 00:00:00

pages

60.e1-60.e17

issue

eissn

0002-9378

issn

1097-6868

pii

S0002-9378(16)30779-7

journal_volume

216

pub_type

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Lactate produced during labor modulates uterine inflammation via GPR81 (HCA1).